COVID-19 does not impact on outcome of myeloma patients infected while undergoing autologous stem cell transplantation.

Here we report two cases of myeloma patients who became positive for SARS-CoV-2 infection during the acute phase of autologous stem cell transplant. Both patients were promptly treated with monoclonal antibodies and remdesivir, and, despite the profound neutropenia and lymphopenia, they did not develop respiratory failure and they remained paucisymptomatic during the entire period of aplasia. Neutrophil engraftment took place as expected and the patients were discharged quickly and did not experience adverse effects after discharge.

Clinical features and prognostic factors of Magnusiomyces (Saprochaete) infections in haematology. A multicentre study of SEIFEM/Fungiscope.

BACKGROUND: Our multicentre study aims to identify baseline factors and provide guidance for therapeutic decisions regarding Magnusiomyces-associated infections, an emerging threat in patients with haematological malignancies. METHODS: HM patients with proven (Magnusiomyces capitatus) M. capitatus or (Magnusiomyces clavatus) M. clavatus (formerly Saprochaete capitata and Saprochaete clavata) infection diagnosed between January 2010 and December 2020 were recorded from the SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) group and FungiScope (Global Emerging Fungal Infection Registry). Cases of Magnusiomyces fungemia were compared with candidemia. RESULTS: Among 90 Magnusiomyces cases (60 [66%] M. capitatus and 30 (34%) M. clavatus), median age was 50 years (range 2-78), 46 patients (51%) were female and 67 (74%) had acute leukaemia. Thirty-six (40%) of Magnusiomyces-associated infections occurred during antifungal prophylaxis, mainly with posaconazole (n = 13, 36%) and echinocandins (n = 12, 34%). Instead, the candidemia rarely occurred during prophylaxis (p < .0001). First-line antifungal therapy with azoles, alone or in combination, was associated with improved response compared to other antifungals (p = .001). Overall day-30 mortality rate was 43%. Factors associated with higher mortality rates were septic shock (HR 2.696, 95% CI 1.396-5.204, p = .003), corticosteroid treatment longer than 14 days (HR 2.245, 95% CI 1.151-4.376, p = .018) and lack of neutrophil recovery (HR 3.997, 95% CI 2.102-7.601, p < .001). The latter was independently associated with poor outcome (HR 2.495, 95% CI 1.192-5.222, p = .015). CONCLUSIONS: Magnusiomyces-associated infections are often breakthrough infections. Effective treatment regimens of these infections remain to be determined, but neutrophil recovery appears to play an important role in the favourable outcome.

A High-Risk Profile for Invasive Fungal Infections Is Associated with Altered Nasal Microbiota and Niche Determinants.

It is becoming increasingly clear that the communities of microorganisms that populate the surfaces exposed to the external environment, termed microbiota, are key players in the regulation of pathogen-host cross talk affecting the onset as well as the outcome of infectious diseases. We have performed a multicenter, prospective, observational study in which nasal and oropharyngeal swabs were collected for microbiota predicting the risk of invasive fungal infections (IFIs) in patients with hematological malignancies. Here, we demonstrate that the nasal and oropharyngeal microbiota are different, although similar characteristics differentiate high-risk from low-risk samples at both sites. Indeed, similar to previously published results on the oropharyngeal microbiota, high-risk samples in the nose were characterized by low diversity, a loss of beneficial bacteria, and an expansion of potentially pathogenic taxa, in the presence of reduced levels of tryptophan (Trp). At variance with oropharyngeal samples, however, low Trp levels were associated with defective host-derived kynurenine production, suggesting reduced tolerance mechanisms at the nasal mucosal surface. This was accompanied by reduced levels of the chemokine interleukin-8 (IL-8), likely associated with a reduced recruitment of neutrophils and impaired fungal clearance. Thus, the nasal and pharyngeal microbiomes of hematological patients provide complementary information that could improve predictive tools for the risk of IFI in hematological patients.

Invasive aspergillosis in relapsed/refractory acute myeloid leukaemia patients: Results from SEIFEM 2016-B survey.

BACKGROUND: In patients with relapsed/refractory acute myeloid leukaemia (R/R AML) who received salvage chemotherapy, limited and not updated studies explored the incidence of invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP). The aims of this multicentre retrospective 'SEIFEM 2016-B' study were as follows: (1) to evaluate the current rate and the outcome of proven/probable IA and (2) to assess the efficacy of AP, in a large 'real life' series of patient with R/R AML submitted to salvage chemotherapy. RESULTS: Of 2250 R/R AML patients, a total of 74 cases of IA (5.1%) were recorded as follows: 10 (0.7%) proven and 64 (4.3%) probable. Information about AP were available in 73/74 (99%) patients. Fifty-eight (79%) breakthrough infections occurred, mainly during AP with posaconazole [25 (43%)]. The patients who received AP during salvage chemotherapy showed a benefit from antifungal therapy (AT) than patients who did not received AP [43 (86%) vs 7 (14%); p < .033]. In a multivariate analysis, AP and absence of severe mucositis had a significant favourable effect on overall response rate. CONCLUSION: Our data demonstrated that the incidence of IA during the salvage chemotherapy is similar to the past. Nevertheless, the attributable mortality rate (AMR) appears to be lower than that previously reported in R/R AML. Further prospective studies should be performed to confirm our preliminary observation and understand and the why a decreased AMR is reported in this setting of high-risk patients.

Pharyngeal Microbial Signatures Are Predictive of the Risk of Fungal Pneumonia in Hematologic Patients.

The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological patients, whether airway dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and stratified according to the risk of developing IFI. A lower microbial richness and evenness were found in the pharyngeal microbiota of high-risk patients that were associated with a distinct taxonomic and metabolic profile. A murine model of IFI provided biologic plausibility for the finding that loss of protective anaerobes, such as Clostridiales and Bacteroidetes, along with an apparent restricted availability of tryptophan, is causally linked to the risk of IFI in hematologic patients and indicates avenues for antimicrobial stewardship and metabolic reequilibrium in IFI.

Infections in patients with lymphoproliferative diseases treated with targeted agents: SEIFEM multicentric retrospective study.

We describe the opportunistic infections occurring in 362 patients with lymphoproliferative disorders treated with ibrutinib and idelalisib in clinical practice. Overall, 108 of 362 patients (29·8%) developed infections, for a total of 152 events. Clinically defined infections (CDI) were 49·3% (75/152) and microbiologically defined infections (MDI) were 50·7% (77/152). Among 250 patients treated with ibrutinib, 28·8% (72/250) experienced one or more infections, for a total of 104 episodes. MDI were 49% (51/104). Bacterial infections were 66·7% (34/51), viral 19·6% (10/51) and invasive fungal diseases (IFD) 13·7% (7/51). Among the 112 patients treated with idelalisib, 32·1% (36/112) experienced one or more infections, for a total of 48 episodes. MDI were 54·2% (26/48). Bacterial infections were 34·6% (9/26), viral 61·5% (16/26) and IFD 3·8% (1/26). With ibrutinib, the rate of bacterial infections was significantly higher compared to idelalisib (66·7% vs. 34·6%; P = 0·007), while viral infections were most frequent in idelalisib (61·5% vs. 19·6%; P < 0·001). Although a higher rate of IFD was observed in patients treated with ibrutinib, the difference was not statistically significant (13·7% vs. 3·8% respectively; P = 0·18). Bacteria are the most frequent infections with ibrutinib, while viruses are most frequently involved with idelalisib.

Rhodotorula infection in haematological patient: Risk factors and outcome.

BACKGROUND: Rhodotorula spp are uncommon yeasts able to cause infections with high mortality rates. Rhodotorula infections have been associated with the presence of central venous catheter (CVC), immunosuppression, exposure to antifungals and the presence of either solid or haematologic malignancies. However, in this latter setting, only a few cases have so far been reported. OBJECTIVES: We have conducted a survey for Rhodotorula infections in haematologic patients. METHODS: Patients' clinical and microbiological data were collected and correlated to the outcome. RESULTS: A total of 27 cases were detected from 13 tertiary care hospitals. About 78% and 89% of patients had acute leukaemia and CVC. About 70% of patients were exposed to prophylaxis with azoles, mainly posaconazole (37%), 59% were severely neutropenic and 37% underwent allogeneic stem cell transplantation (alloSCT). The most frequent treatments were liposomal amphotericin B (L-AmB) and CVC removal in 17 and 16 patients, respectively. One month post-diagnosis, mortality was 26% and was associated with the presence of mucositis (P = 0.034). CONCLUSIONS: Our study shows that Rhodotorula spp should be considered as aetiologic agents of breakthrough infections in acute leukaemia patients with a CVC, mucositis, who receive prophylaxis with azoles, including posaconazole, and/or undergo alloSCT. Prompt measures, such as L-AmB administration and CVC removal, should be carried out to avoid the high mortality risk of Rhodotorula infections.

Febrile events in acute lymphoblastic leukemia: a prospective observational multicentric SEIFEM study (SEIFEM-2012/B ALL).

The purpose of the present study is to estimate the current incidence of febrile events (FEs) and infectious episodes in acute lymphoblastic leukemia (ALL) and evaluate the outcome. We analyzed data on all FEs in a cohort of patients affected by ALL admitted to 20 Italian hematologic centers during 21 months of observation from April 1, 2012 to December 31, 2013. Data about treatment phase, steroids, neutropenia, type and site of infection, and outcome of infection were collected. The population comprehended 271 ALL adult patients. Median age was 46 years old (range 19-75), M/F 1.1:1. We collected 179 FEs occurring during 395 different phases of treatment in 127 patients (45.3% incidence): remission induction treatment 53.1%, consolidation/maintenance 35.7%, treatment for a first or second relapse 44.3%, and refractory disease 85.7%. The incidence of FUO (fever of unknown origin) was 55/395 (13.9%). In the remaining cases, bacteria caused 92 FEs (23.2%), fungi 17 (4.3%), viruses 5 (1%). Mixed infections occurred in 10 cases mainly fungal+bacterial (9/10 cases). Neutropenia was mostly present at onset of FE (89.9% of FEs). Mortality rate was 11.7% (21/179) while 16 deaths occurred with evidence of infection (8.9%). Age > 60 years, neutropenia, poor performance status, steroids, refractory disease, and mixed infections significantly correlated with infection-related mortality. A statistically significant association with mortality was observed also for pulmonary localization and bacteremia. Our study describes the real-life epidemiological scenario of infections in ALL and identifies a subset of patients who are at higher risk for infection-related mortality.

Second Neoplasms in Italian Patients with Hairy Cell Leukemia after Treatment with Cladribine: A Multicenter Investigation and Literature Review.

Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence ratios (SIRs). We identified 24 patients with a second cancer diagnosed at a median time from treatment with cladribine of 59.9 months (range: 9.2-169.7 months). All patients with solid neoplasms presented with a limited-stage disease, except four cases of locally advanced cancer; multiple myeloma patients had a smoldering disease, while lymphoma patients had stage Ie and stage IV diseases. Response to therapy was complete in 19 cases; 1 patient is still receiving treatment for a relapsing bladder disease, while 2 patients progressed during treatment and died. These two patients died from unrelated causes: one from infection and one due to surgery complications. The median OS from HCL was 98.5 months (range: 38.4-409.2 months), while the median OS from second cancer was 27.6 months (range: 1-117.8 months). The SIR was 0.86 (95% CI: 0.54-1.30) for males and 1.13 (95% CI: 0.36-2.73) for females: no statistically significant differences were highlighted. We were not able to demonstrate an excess of second cancer or a significant association with the specific studied neoplasm.

Bloodstream infections due to Gram-negative bacteria in patients with hematologic malignancies: updated epidemiology and risk factors for multidrug-resistant strains in an Italian perspective survey.

Bloodstream infections (BSI) caused by Gram-negative bacteria (GNB) in patients with hematological malignancies (HM) have been associated with high mortality rates, particularly with infections caused by antibiotic-resistant strains. A multicenter cohort study including all consecutive episodes of GNB BSI in HM patients was conducted to update the epidemiology and antibiotic resistance patterns (compared to our previous survey conducted between 2009 and 2012) and investigate risk factors for GNB BSI due to multidrug-resistant (MDR) isolates. A total of 834 GNB were recovered in 811 BSI episodes from January 2016 to December 2018. Compared to the previous survey, there was a significant reduction in use of fluoroquinolone prophylaxis and a significant recovery in susceptibility rates to ciprofloxacin among Pseudomonas aeruginosa, Escherichia coli and Enterobacter cloacae isolates. In addition, there was a shift to a significantly increased susceptibility of P. aeruginosa isolates to ceftazidime, meropenem, and gentamicin. A total of 256/834 (30.7%) isolates were MDR. In multivariable analysis, MDR bacteria culture-positive surveillance rectal swabs, previous therapy with aminoglycosides and carbapenems, fluoroquinolone prophylaxis, and time at risk were independently associated with MDR GNB BSI. In conclusion, despite the persistence of a high prevalence of MDR GNB, there was a shift to a reduced use of fluoroquinolone prophylaxis and increased rates of susceptibility to fluoroquinolones in almost all isolates and to almost all antibiotics tested among P. aeruginosa isolates, compared to our previous survey. Fluoroquinolone prophylaxis and previous rectal colonization by MDR bacteria were independent risk factors for MDR GNB BSI in the present study.

Long-term follow-up of cladribine treatment in hairy cell leukemia: 30-year experience in a multicentric Italian study.

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24-88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value (p = 0.044), frequency of circulating hairy cells (p = 0.039), recovery of absolute neutrophil count (p = 0.006), and normalization of spleen (p ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04-28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p < 0.0001). Non-hematological grade 3 or higher early toxicity was reported in 103 (20.1%) patients. Median OS was not reached: 95.3%, 92.4%, and 81.8% of patients were estimated to be alive at 5, 10, and 15 years, respectively. Forty-nine patients died (9.5%), following an infection in 14 cases (2.7%), natural causes in 14 (2.7%), cardiovascular events in 13 (2.5%), a second neoplasm in 6 (1.2%), and progression of HCL in 2 cases (0.4%). Following treatment of HCL with 2CDA, 80% of patients are estimated to be alive 15 years after diagnosis.

Considerations on antimicrobial prophylaxis in patients with lymphoproliferative diseases: A SEIFEM group position paper.

The therapeutic armamentarium for the treatment of patients with lymphoproliferative diseases has grown considerably over the most recent years, including a large use of new immunotherapeutic agents. As a consequence, the epidemiology of infectious complications in this group of patients is poorly documented, and even more importantly, the potential benefit of antimicrobial prophylaxis remains a matter of debate when considering the harmful effect from the emergence of multidrug resistant pathogens. The present position paper is addressed to all hematologists treating patients affected by lymphoproliferative malignancies with the aim to provide clinicians with a useful tool for the prevention of bacterial, fungal and viral infections.

Bloodstream infections caused by Escherichia coli in onco-haematological patients: Risk factors and mortality in an Italian prospective survey.

Bloodstream infections (BSIs) remain life-threatening complications in the clinical course of patients with haematological malignancies (HM) and Escherichia coli represent one of the most frequent cause of such infections. In this study, we aimed to describe risk factors for resistance to third generation cephalosporins and prognostic factors, including the impact of third generation cephalosporins resistance, in patients with HM and BSIs caused by E. coli. Three hundred forty-two cases of E. coli BSIs were collected during the study period (from January 2016 to December 2017). The percentage of resistance to third generation cephalosporins was 25.7%. In multivariate analysis, the variables recent endoscopic procedures, culture-positive surveillance rectal swabs for multidrug-resistant bacteria, antibiotic prophylaxis with fluoroquinolones, and prolonged neutropenia were independently associated with bloodstream infections caused by a third generation cephalosporins resistant E. coli. The overall 30-day mortality rate was 7.1%. Cox regression revealed that significant predictors of mortality were acute hepatic failure, septic shock, male sex, refractory/relapsed HM, and third generation cephalosporins resistance by E. coli isolate. In conclusion, resistance to third generation cephalosporins adversely affected the outcomes of bloodstream infections caused by E. coli in our cohort of HM patients. We also found a significant correlation between prophylaxis with fluoroquinolones and resistance to third generation cephalosporins by E. coli isolates.

Haploidentical hematopoietic stem cell transplantation in adults using the αßTCR/CD19-based depletion of G-CSF-mobilized peripheral blood progenitor cells.

In patients with hematological malignancies at high risk for relapse, a mismatched hematopoietic stem cells transplants can be offered with no undue delay between decision-making and transplantation as virtually all patients have a full-haplotype mismatched member who could serve immediately as a donor. Using a T-cell depletion approach, these patients can benefit from a graft-vs-leukemia effect in the absence of both acute and chronic graft-vs-host disease. Over the past decade, efforts have concentrated on developing new conditioning regimens, optimizing the graft processing and improving the posttransplant immunological recovery. The innovative strategy based on the selective depletion of alpha/beta-positive T lymphocytes from G-CSF-mobilized peripheral blood precursor cells has shown very promising results in the setting of the pediatric transplantation. This paper reports the outcome in adult patients with hematological malignancies.

Isavuconazole in Hematological Patients: Results of a Real-Life Multicentre Observational Seifem Study.

Invasive fungal diseases (IFDs) remain a major clinical issue in patients with hematological malignancies (HMs). To confirm the efficacy and safety of the new azole isavuconazole (ISV) in a clinical care setting, we planned a multicenter retrospective study; we collected data on all possible/probable/proven IFDs in patients with HMs treated with ISV in 17 centers. Between July 2016 and November 2018, 128 patients were enrolled, and 122 were fully evaluable. ISV was employed as the 1st line therapy in 43 (35%) patients and as a subsequent therapy in 79 (65%) patients. The response rate was 82/122 patients (67.2%); it was similar when using ISV as a 1st or 2nd line treatment (60.5% vs 70.9%, respectively; p = 0.24). In multivariate analysis, both female sex (OR: 2.992; CI: 1.22-7.34) and induction phase of treatment (OR: 3.953; CI: 1.085-14.403) were predictive of a favorable response. At a median follow-up of 5 months, 43 (35.2%) patients were dead; the 1-year overall survival (OS) was 49.9%. In multivariate analysis, the response to ISV (OR: 0.103; CI: 0.041-0.262) and IFD refractoriness to previous antifungals (OR: 3.413; CI: 1.318-8.838) were statistically significant for OS. Adverse events (AEs) were reported in 15/122 patients (12.3%); grade 3-4 AEs were reported in 5 (4%) and led to ISV discontinuation. Our study confirms the safety and tolerability of ISV, also in diseases other than acute leukemia. Phase of hematological disease, gender and refractoriness to previous antifungals are the main predictive factors for the aforementioned response and outcome.

Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans.

Aspergillus is the causative agent of human diseases ranging from asthma to invasive infection. Genetic and environmental factors are crucial in regulating the interaction between the host and Aspergillus. The role played by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the first and rate-limiting step of tryptophan catabolism along the kynurenine pathway, is increasingly being recognized, but whether and how genetic variation of IDO1 influences the risk of aspergillosis in susceptible patients is incompletely understood. In addition, whether the closely related protein IDO2 plays a similar role remains unexplored. In the present study, we performed genetic association studies in two different cohorts of susceptible patients [cystic fibrosis (CF) patients and recipients of hematopoietic stem cell transplantation (HSCT)], and identified IDO1 polymorphisms that associate with the risk of infection in both cohorts. By using human bronchial epithelial cells and PBMC from CF and HSCT patients, respectively, we could show that the IDO1 polymorphisms appeared to down-modulate IDO1 expression and function in response to IFNγ or Aspergillus conidia, and to associate with an increased inflammatory response. In contrast, IDO2 polymorphisms, including variants known to profoundly affect protein expression and function, were differently associated with the risk of aspergillosis in the two cohorts of patients as no association was found in CF patients as opposed to recipients of HSCT. By resorting to a murine model of bone marrow transplantation, we could show that the absence of IDO2 more severely affected fungal burden and lung pathology upon infection with Aspergillus as compared to IDO1, and this effect appeared to be linked to a deficit in the antifungal effector phagocytic activity. Thus, our study confirms and extends the role of IDO1 in the response to Aspergillus, and shed light on the possible involvement of IDO2 in specific clinical settings.

Maintenance of renal function in a patient with a history of acute paroxysmal nocturnal hemoglobinuria-associated kidney injury.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by intravascular hemolysis, thrombosis and bone marrow failure. Acute kidney injury, including acute renal failure, have been reported in patients with PNH. We report the case of a 36-year-old male patient with PNH who developed acute kidney injury following an infection of undetermined diagnosis. Although hemolysis was initially controlled and renal function stabilized following packed red blood cell transfusion and empirical levofloxacin and prednisone, he later experienced recurrent episodes of hemolysis and hematuria requiring monthly red blood cell support. Given the high risk of thromboembolic events, treatment with standard-dose eculizumab was started. The patient's hematologic values improved, renal function was maintained, and no thromboembolic events occurred.

SEIFEM 2017: from real life to an agreement on the use of granulocyte transfusions and colony-stimulating factors for prophylaxis and treatment of infectious complications in patients with hematologic malignant disorders.

INTRODUCTION: The rapid spread of severe infections mainly due to resistant pathogens, justifies the search for therapies aiming to restore immune functions severely compromised in patients with hematologic malignancies. Areas covered: The present review summarizes the current knowledge on the role of granulocyte transfusions and colony-stimulating factors as treatment strategy for hematologic patients with serious infectious complications. In addition, a survey among 21 hematologic centers, to evaluate the clinical practice for the use of G-CSF originator and biosimilars was performed. Expert commentary: Granulocyte transfusions with a target dose of at least 1.5-3 × 108 cells/kg, may be considered as an approach to bridge the gap between marrow suppression and recovery of granulocytes. G-CSF shortens the period of neutropenia, the hospitalization, the use of antibiotics and the rate of febrile neutropenia (FN) in adult and pediatric patients with non-Hodgkin lymphoma, and in adults with acute myeloid leukemia where these advantages nevertheless, did not translate into a clinical benefit. G-CSF biosimilar showed equivalence or non-inferiority to filgrastim. There are no data supporting the use of GM-CSF, eltrombopag and erythropoietin for preventing or treating infectious complications in patients with hematologic disorders.

Immunity to Infections after Haploidentical Hematopoietic Stem Cell Transplantation.

The advantage of using a Human Leukocyte Antigen (HLA)-mismatched related donor is that almost every patient who does not have an HLA-identical donor or who urgently needs hematopoietic stem cell transplantation (HSCT) has at least one family member with whom shares one haplotype (haploidentical) and who is promptly available as a donor. The major challenge of haplo-HSCT is intense bi-directional alloreactivity leading to high incidences of graft rejection and graft-versus-host disease (GVHD). Advances in graft processing and pharmacologic prophylaxis of GVHD have reduced these risks and have made haplo-HSCT a viable alternative for patients lacking a matched donor. Indeed, the haplo-HSCT has spread to centers worldwide even though some centers have preferred an approach based on T cell depletion of G-CSF-mobilized peripheral blood progenitor cells (PBPCs), others have focused on new strategies for GvHD prevention, such as G-CSF priming of bone marrow and robust post-transplant immune suppression or post-transplant cyclophosphamide (PTCY). Today, the graft can be a megadose of T-cell depleted PBPCs or a standard dose of unmanipulated bone marrow and/or PBPCs. Although haplo-HSCT modalities are based mainly on high intensity conditioning regimens, recently introduced reduced intensity regimens (RIC) showed promise in decreasing early transplant-related mortality (TRM), and extending the opportunity of HSCT to an elderly population with more comorbidities. Infections are still mostly responsible for toxicity and non-relapse mortality due to prolonged immunosuppression related, or not, to GVHD. Future challenges lie in determining the safest preparative conditioning regimen, minimizing GvHD and promoting rapid and more robust immune reconstitution.

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1.

Defects in a form of noncanonical autophagy, known as LC3-associated phagocytosis (LAP), lead to increased inflammatory pathology during fungal infection. Although LAP contributes to fungal degradation, the molecular mechanisms underlying LAP-mediated modulation of inflammation are unknown. We describe a mechanism by which inflammation is regulated during LAP through the death-associated protein kinase 1 (DAPK1). The ATF6/C/EBP-ß/DAPK1 axis activated by IFN-γ not only mediates LAP to Aspergillus fumigatus but also concomitantly inhibits Nod-like receptor protein 3 (NLRP3) activation and restrains pathogenic inflammation. In mouse models and patient samples of chronic granulomatous disease, which exhibit defective autophagy and increased inflammasome activity, IFN-γ restores reduced DAPK1 activity and dampens fungal growth. Additionally, in a cohort of hematopoietic stem cell-transplanted patients, a genetic DAPK1 deficiency is associated with increased inflammation and heightened aspergillosis susceptibility. Thus, DAPK1 is a potential drugable player in regulating the inflammatory response during fungal clearance initiated by IFN-γ.